Drug Class Update with New Drug Evaluation: Acne Drugs

Drug Use Research & Management Program Oregon State University, 500 Summer Street NE, E35 Salem, Oregon 97301-1079 Phone 503-947-5220 | Fax 503-947-2596

Date of Review: June 2020 Date of Last Review: November 2018 Dates of Literature Search: 08/03/2018 - 12/26/2019 Generic Name: Trifarotene Brand Name (Manufacturer): Aklief® (Galderma Laboratories, LP) Dossier Received: no

Current Status of PDL Class: See Appendix 1.

Purpose for Class Update: The acne class has had one new approval, trifarotene cream, and several new product formulations since it was last reviewed in 2018. The purpose of this update is to evaluate new comparative evidence for trifarotene cream for the treatment of acne vulgaris and any new data on comparative efficacy or harms in the acne class since the previous update. Acne conglobata, acne fulminans, and severe cystic acne are covered conditions under the Oregon Health Plan (OHP).

Research Questions: 1. What is the comparative efficacy and effectiveness of treatments for severe acne (topical agents of adapalene, adapalene/benzoyl peroxide, tretinoin, tazarotene, benzoyl peroxide, salicylic acid, dapsone, azelaic acid, clindamycin, erythromycin, minocycline, sulfacetamide, trifarotene; oral systemic antibiotics of doxycycline, minocycline, tetracycline, azithromycin, erythromycin, clindamycin, trimethoprim, and sulfamethoxazole/trimethoprim; hormonal agents of oral contraceptives and spironolactone; and oral isotretinoin)? 2. What are the comparative harms of treatments for severe acne? 3. Are there subpopulations of patients in which a particular treatment for severe acne would be more effective or associated with less harm?

Conclusions:  There are no new high-quality clinical practice guidelines which have evaluated comparative efficacy and safety of treatments for acne vulgaris.  Two high quality systematic reviews evaluated comparative efficacy and safety of oral isotretinoin with other acne vulgaris treatments. These reviews contain low- and very low-quality evidence due to various biases and methodological study limitations.  There are no new randomized trials studying comparative efficacy and harms between treatment regimens for acne vulgaris.  There is insufficient evidence to determine comparative efficacy and safety of treatments for severe acne.  With the exception of oral isotretinoin, there is insufficient evidence to determine if any subpopulations would particularly benefit or be harmed by a particular treatment for severe acne.

Author: Sara Fletcher, PharmD, MPH, BCPS

 Trifarotene has moderate quality evidence due to study limitations to support its use in moderate acne vulgaris. Quality is limited by unclear selection bias, high attrition bias, and bias related to industry funding. Applicability is limited by lack of racial diversity in study population and limitations related to placebo control rather than active control. Number needed to treat of 6 to 10 for treatment success as defined by trial protocol.

Recommendations:  Maintain non-preferred designation for trifarotene cream and other new single-source brand formulations on PDL given lack of high-quality data to support use in severe acne.  No other PDL recommendations based on clinical evidence.  Evaluate costs in the executive session.

Summary of Prior Reviews and Current Policy  This drug class review is limited by the lack of high-quality evidence from high quality systematic reviews and guidelines which evaluate the comparative efficacy and safety of treatments for severe acne.  There are also limited randomized controlled trials in the severe acne population and the majority of the trials are older with methodological and conflict of interest concerns.  There is insufficient evidence to determine comparative efficacy and safety of treatments for severe acne.  There is insufficient evidence to determine if any subpopulations would particularly benefit or be harmed by a particular treatment for severe acne.  Though not of high methodological quality due to conflict of interest concerns, recent guidelines from the American Academy of Dermatology, European Academy of Dermatology and Venereology, and American Academy of Pediatrics recommend multiple treatment options for severe acne, all including isotretinoin. Other recommended treatments include combination therapy with systemic antibiotics and topical therapies such as benzoyl peroxide, retinoids, or topical antibiotics. Recommendations for treatment of mild to moderate acne generally includes the same therapies, either as monotherapy or in differing combinations, but isotretinoin is generally not recommended until acne is severe.  Isotretinoin has substantial safety concerns compared to other medications for acne. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking isotretinoin. Because of the teratogenicity risk, it is approved for marketing only under a REMS program called iPLEDGE™.  Prior authorization (PA) criteria for the Acne preferred drug list (PDL) class, includes federal legend topical medications that have an Food and Drug Administration (FDA) approved and OHA-funded indication for severe acne vulgaris and oral isotretinoin. Use is limited to funded conditions (Appendix 6).  All single source brand agents are non-preferred and all other agents in the Acne PDL class are preferred.

Background: Acne vulgaris (AV) is a chronic skin condition that affects approximately 50 million people in the United States.1 It most commonly affects adolescents and young adults, but can continue into adulthood. Morbidity associated with acne can include permanent scarring, poor self-image, depression, and anxiety.1 Acne vulgaris is characterized by noninflammatory open or closed comedones and inflammatory lesions.2 These are generally located on the face, neck, back, chest, and upper arms.2,3 Follicular hyperkeratinization, microbial colonization with Cutibacterium acnes (formerly Propionibacterium acnes), sebum production, and inflammatory factors involving innate and acquired immunity are all involved in the pathology of this condition.1,2

Author: Fletcher June 2020

While there is no universal grading system, and as many as 18 different grading scales are used in the literature, classification of acne is commonly described as mild, moderate, or severe.1,3,4 These are delineated by frequency of papules or pustules and presence and frequency of nodules, as well as presence of hyperpigmentation and erythema.3 The Physician’s Global Assessment (PGA) is a 5-point scale (0-4) that was previously recommended by the FDA to evaluate success in clinical trials of acne vulgaris treatment.5 The scale defines the skin as clear, almost clear, mild, moderate, and severe with corresponding descriptions for each score based on number of comedones, papules, pustules, nodules, cysts and overall amount of face involved.5 More recently, the FDA has given industry guidance to use the Investigator’s Global Assessment (IGA) as an ordinal scale to assess overall severity.6 The IGA is a 5- or 6-point scale (0-5) that grades hyperpigmentation and erythema as clear, almost clear, mild, moderate, severe, and very severe.6 It should be used in conjunction with separate counting of inflammatory and noninflammatory lesions.6

Acne conglobata and acne fulminans are two forms of severe acne. Acne conglobata is a severe form of nodular acne that involves recurrent abscesses and communicating sinuses and often results in disfiguring scars.3 Acne fulminans is a severe variant of inflammatory acne that presents with severe ulceration and occasionally the systemic symptoms of fever and arthralgia.3 Assessment is done by physical exam and includes a pattern-diagnosis system that evaluates not only the presence and frequency of certain lesions, but also complications such as drainage, hemorrhage, pain and other factors like occupational disability, psychosocial impact, and failure of response to previous therapies.3

Treatment for acne may include a variety of agents such as topical medications (i.e., retinoids, benzoyl peroxide, topical antibiotics, salicylic acid, azelaic acid, sulfacetamide), systemic or topical antibiotics (i.e., doxycycline, minocycline, erythromycin, azithromycin, clindamycin, trimethoprim, dapsone), hormonal agents (i.e. oral contraceptives, spironolactone, antiandrogens), and oral isotretinoin.1,2,7 Choice of treatment depends on severity of disease. Isotretinoin, which has an associated iPLEDGE REMS program, is specifically FDA-approved for severe recalcitrant nodular acne and recommended for severe acne.2,7 Other treatments for severe acne usually include combination therapy with multiple classes of medications which can also be used for mild or moderate acne.2,7 These classes of medications are well-established and all have been FDA-approved for many years.

Clinically meaningful outcomes for acne assessment include quality of life (QoL) and symptom reduction as demonstrated by decreased lesion counts or lessened acne severity. There are no QoL assessment tools recommended in the FDA guidance to industry6, nor was it included in the current new drug evaluation. Development and validation of a patient reported outcome measure for assessing acne treatment in the clinic is an identified research gap.1 Though there seems to be no universally determined minimal clinically important difference for these outcomes, a consensus view of the authors of the European Evidence-Based Guidelines for Treatment of Acne suggested a minimal clinically important difference of 10% or greater reduction in lesion count as an efficacy outcome.8 A final IGA assessment of 0 to 1 (clear to almost clear) and at least a 2-grade improvement from baseline is defined by the FDA as a clinically meaningful outcome.6

Prior authorization (PA) criteria for the Acne preferred drug list (PDL) class, includes federal legend topical medications that have FDA approval and an OHA- funded indication for severe acne vulgaris and oral isotretinoin. Use is limited to funded conditions in the OHP (Appendix 6).

Table 1: Acne class prior authorization requests Time Period Medication request number Approval number Denial number 4th Quarter 2019 99 (1 cancelled) 50 (51%) 48 (48%) 3rd Quarter 2019 39 26 (67%) 12 (31%) 2nd Quarter 2019 71 45 (63%) 26 (37%) 1st Quarter 2019 101 (1 cancelled) 50 (50%) 50 (50%) Author: Fletcher June 2020

Methods: A Medline literature search for new systematic reviews and randomized controlled trials (RCTs) assessing clinically relevant outcomes to active controls, or placebo if needed, was conducted. The Medline search strategy used for this review is available in Appendix 3, which includes dates, search terms and limits used. The OHSU Drug Effectiveness Review Project, Agency for Healthcare Research and Quality (AHRQ), National Institute for Health and Clinical Excellence (NICE), Department of Veterans Affairs, and the Canadian Agency for Drugs and Technologies in Health (CADTH) resources were manually searched for high quality and relevant systematic reviews. When necessary, systematic reviews are critically appraised for quality using the AMSTAR tool and clinical practice guidelines using the AGREE tool. The FDA website was searched for new drug approvals, indications, and pertinent safety alerts.

The primary focus of the evidence is on high quality systematic reviews and evidence-based guidelines. Randomized controlled trials will be emphasized if evidence is lacking or insufficient from those preferred sources.

Systematic Reviews:

After review, 2 systematic reviews were excluded due to poor quality9,10 (e.g, indirect network-meta analyses), wrong study design of included trials (e.g., observational), comparator (e.g., no control or placebo-controlled), or outcome studied (e.g., non-clinical).

Cochrane-Oral isotretinoin for acne The safety and efficacy of oral isotretinoin for acne vulgaris was assessed in a 2018 Cochrane review.11 Thirty-one RCTs (n=3836) of patients aged 12-55 years with mild to severe acne were included.11 Oral isotretinoin was compared to placebo and other therapies for acne vulgaris.11 These trials were conducted in Asia, Europe, and North America, and outcomes were measured between weeks 8-32 of therapy.11 All studies but three had a high risk of bias in at least one domain, and 12 of 16 studies were funded by pharmaceutical companies.11 Additionally, 8 nonrandomized studies were included in the safety data for reporting serious adverse effects.11

Three studies (n=400) were included to assess a primary outcome of efficacy of oral isotretinoin versus a combination of oral antibiotics plus topical therapy in patients with moderate to severe acne.11 Outcomes were assessed at the end of 20 to 24 weeks of treatment.11 Investigator-assessed inflammatory lesion count was no different between isotretinoin versus comparator groups [Relative risk (RR) 1.01; 95% Confidence interval (95% CI), 0.96 to 1.06; n=400; 3 studies], though isotretinoin may slightly improve acne severity by the physician’s global evaluation (RR 1.15; 95% CI, 1.00 to 1.32; n=351; 2 studies).11 Risk of less serious side effects was higher with isotretinoin (RR 1.67; 95% CI 1.42 to 1.98; n=351; 2 studies). The severe side effect of Stevens-Johnson syndrome was seen once in an isotretinoin patient (RR 3.00; 95% CI, 0.12 to 72.98; n=400; 3 studies).11 These outcomes were all from low- or very low-quality evidence.11

Another primary efficacy outcome involved treatment response based on differing oral isotretinoin doses (Table 2).11 All outcomes were graded as low-quality evidence.11 Heterogeneity in the studies precluded a meta-analysis of alternative dose regimens of isotretinoin.11

Author: Fletcher June 2020

Table 2.11 Isotretinoin Dose Response Study/Doses Result Time of assessment Study 1, severe acne (n=154) Decrease in total inflammatory lesion count 20 weeks  0.05 mg/kg/d  79%  0.1 mg/kg/d  80%  0.2 mg/kg/d  84% Study 2, severe acne (n=150) 95% decrease in total inflammatory lesion count 20 weeks  0.1 mg/kg/d  58%  0.5 mg/kg/d  80%  1 mg/kg/d  90% Study 3, moderate acne (n=40) Decrease in total inflammatory lesion count 24 weeks  (A) 0.25-0.4 mg/kg/d continuous low-dose  [(A) vs. (C)], MD 3.72 lesions; 95% CI, 2.13 to 5.31  (B) 0.5-0.7 mg/kg/d continuous conventional dose  [(B) vs. (C)], MD 3.87 lesions; 95% CI, 2.31 to 5.43  (C) 0.5-0.7 mg/kg/d one week each month, intermittent regimen Abbreviations: MD = mean difference; mg/kg/d = milligrams per kilogram per day; 95% CI = 95% confidence interval

No serious adverse events were seen in studies comparing different dosing regimens of isotretinoin (n=906, 14 studies) during treatment duration of 12 to 32 weeks or during follow-up after treatment for up to 48 weeks.11 Heterogeneity prevented meta-analysis of less serious adverse effects (n=858, 13 studies) such as skin dryness, hair loss, or itching.11 Safety outcomes were graded as low- to very low-quality evidence.11

British Journal of Dermatology-Efficacy and adverse events of oral isotretinoin for acne The efficacy and safety of oral isotretinoin compared to alternative therapies or placebo in acne vulgaris was assessed in a 2018 British Journal of Dermatology review.12 Eleven RCTs were included (n=760); only one RCT was assessed as low risk of bias in each of the 9 Cochrane criteria for study quality, while 3 qualified as low risk of bias overall.12 The age range was 18.0 to 47.9 years, 20.5% of patients were female, and most patients had moderate to severe acne.12 The trials had placebo control (n=1); active control with oral antibiotics including minocycline, erythromycin, tetracycline, dapsone, doxycycline, or azithromycin (n=7); alternative retinoid etretinate (n=1); and vitamin B complex (n=1).12 Treatment ranged from 4 weeks to 6 months in duration.12

Seven of 11 trials showed statistical significance (p < 0.05 for the clinical endpoint of a 10% or greater reduction in acne lesion count) compared to the control group (placebo or active control).12 All studies with placebo comparison (n=91) and those with alternative controls (etretinate, n=56; vitamin B complex, n=20) found a statistically and clinically significant improvement in patients treated with oral isotretinoin.12 Results of isotretinoin compared to oral antibiotics (n=593) were more mixed, with only 3 of 7 studies showing statistical significance in favor of isotretinoin treatment.12 Interpretation is also affected by the variety of antibiotic interventions used between different study protocols.12

Adverse reactions were grouped between studies by system given the variation in reporting structure between included trials (Table 3).12 The authors rated the overall quality of evidence from this review as low.12

Table 3. 12 Isotretinoin Adverse Events

Author: Fletcher June 2020

Adverse event frequency Reaction Isotretinoin (n=364) Control (all active and placebo) (n=384) Abnormal blood work 15 5 Dermatological reactions 487 227 Ear, nose, and throat 87 35 Gastrointestinal 15 34 Ophthalmological 54 17 Psychiatric 32 19 Other (headache, increased thirst, musculoskeletal 61 51 pain, tender fingertips, unknown) Total 751 388

New Guidelines:

No new clinical practice guidelines were identified.

New Formulations or Indications:

Tretinoin (Altreno™) 0.05% lotion was approved in August 2018 and is indicated for the topical treatment of acne vulgaris in patients 9 years and older.13 It is a new dosage form of a previously marketed medication.

Minocycline (Amzeeq™) 4% foam was approved in October 2019 to treat inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years and older.14 Administration via foam vehicle is a novel dosage form for this medication.

Tazarotene (Arazlo™) lotion was approved in January 2020 for the treatment of acne vulgaris in patients 9 years and older.15 It is a new dosage form of a previously marketed medication.

Dapsone (Aczone®) 7.5% gel indication was expanded to 9 years of age in September of 2019.16 This labeling change was not applied to the 5% formulation of this medication.

Author: Fletcher June 2020

Table 4. Description of Placebo-Controlled Studies of New Formulations Study Comparison Population Primary Outcome Results Gold et al17 FMX101 (4% minocycline foam) Age 9 years with Coprimary endpoints FMX101 vs vehicle vs. moderate to severe 2 identical studies Placebo vehicle facial acne. (1) Absolute change in Study 04 (04 & 05) inflammatory lesion (1) -14.13 vs. -11.19; LSM difference 2.8; 95% CI 0.72 to 2:1 randomization IGA score = 3 to 4; 20 count from baseline to 4.88; p=0.0083 MC, DB, VC, RCT, to 50 inflammatory week 12. (2) 8.09% vs. 4.77%; RR 1.72; 95% CI 0.73 to 4.05; phase 3 Self-application once daily x 12 lesions; and 25 to 100 p=0.2178 weeks in evening non-inflammatory (2) Rate of IGA- lesions assessed treatment Study 05 Efficacy assessments at weeks 3, success (score of 0 to (1) -13.36 vs. -10.70; LSM difference 3.15; 95% CI 0.95- 6, 9, 12. Study 04 n=466 1 plus at least 2-grade 5.35; p=0.0051 Study 05 n=495 improvement) (2) 14.66% vs. 7.89%; RR 1.88, 95% CI 1.02 to 3.46; Optional open-label continuation p=0.0424 x 40 weeks Tyring et al18 Tretinoin 0.05% lotion Age 9 years with Coprimary endpoints Tretinoin 0.05% lotion vs. vehicle vs. moderate to severe 2 identical studies Placebo vehicle facial acne. (1) Absolute change in (1) LSM 52.1% vs. 41.0%; 95% CI NR; p<0.001 pooled mean inflammatory MC, DB, VC, RCT 1:1 randomization EGSS score of 3 lesion count from (2) LSM 46.1% vs. 29.9%; 95% CI NR; p<0.001 (moderate) or 4 baseline to week 12 Self-application once daily x 12 (severe) and lesion (3) NR weeks counts of 20 to 40 (2) Absolute change in inflammatory lesions mean non- Efficacy assessments at weeks 4, and 20 to 100 noninflammatory lesion 8, 12. inflammatory lesions count from baseline to week 12 n=1640 (3) Proportion of patients with at least 2-grade improvement in EGSS from baseline to week 12

Abbreviations: CI = confidence interval, DB = double blind, EGSS = Evaluator Global Severity Score, IGA = Investigator’s Global Assessment, LSM = least squares mean, MC = multicenter, NR = not reported; RCT = randomized controlled trial, RR = relative risk, VC = vehicle controlled

Author: Fletcher June 2020

New FDA Safety Alerts:

Table 5. Description of New FDA Safety Alerts Generic Name Brand Name Month / Year Location of Change Addition or Change and Mitigation Principles (if of Change (Boxed Warning, applicable) Warnings, CI) Clindamycin Multiple 12/16/2019 Warnings and Precautions Addition of breastfeeding caution (topical) Dapsone Aczone 5/18/2018 Adverse Reactions Identified post-approval reactions for topical product: methemoglobinemia, rash (including erythematous rash, application site rash, and swelling of face (including lip swelling, eye swelling) Isotretinoin Absorica, 5/2/2018 Warnings and Precautions iPLEDGE program: prescriptions must be obtained no later multiple than the “do not dispense to after” date. If not obtained, product must be returned to inventory. Isotretinoin Absorica, 11/7/2019 Boxed Warning Embryo-fetal toxicity and pregnancy contraindication multiple reworded Mequinol/Tretinoin Solage 12/2/2019 Warnings and Precautions Additions of warning of embryo-fetal toxicity, recommendations to use sunscreen and avoid potentially irritating products and weather extremes, and caution of potential to irritate eczematous skin and cause skin fissures added.

Randomized Controlled Trials: A total of 32 citations were manually reviewed from the initial literature search. After further review, 30 citations were excluded because of wrong study design (eg, observational)19-36, comparator (eg, no control or placebo-controlled)37-44, population45,46, or outcome studied (eg, non-clinical)47,48. The remaining 2 trials, which are placebo controlled, include new drug formulations, and are summarized in the table X above. Full abstracts are included in Appendix 2. NEW DRUG EVALUATION:

See Appendix 4 for Highlights of Prescribing Information from the manufacturer, including Boxed Warnings and Risk Evaluation Mitigation Strategies (if applicable), indications, dosage and administration, formulations, contraindications, warnings and precautions, adverse reactions, drug interactions and use in specific populations.

Clinical Efficacy: Trifarotene

Trifarotene is a retinoid cream that is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older.49

Author: Fletcher June 2020

Trifarotene is an agonist of the retinoic acid receptors (RAR), with most affinity at the gamma subtype. This contrasts earlier topical retinoids, which target both the beta and gamma subtypes, though the clinical implication of this affinity is unknown.49,50 Stimulation of RAR is associated with cell differentiation and reduction of inflammation. The exact mechanism for amelioration of acne is unknown.49

Trifarotene has been evaluated in two randomized, multicenter, parallel group, double-blind, vehicle-controlled trials with identical design to assess use for the treatment of moderate facial and truncal acne vulgaris [PERFECT 1 (NCT02566369), PERFECT 2 (NCT02556788)].49,50 Patients aged 9 years and older were treated for up to 12 weeks with trifarotene cream or a placebo vehicle cream.49,50 Patients were encouraged to moisturize either 1 hour before or after study treatment use.49,50 Efficacy was assessed with a 5-point IGA for the face and 5-point PGA for the trunk; it is unclear why PGA was chosen for the truncal assessment.49,50 Moderate acne scores 3 of 5 on these scales.49,50 Treatment success required IGA/PGA scale achievement of both a minimum 2-point improvement from baseline AND a score of 0 (clear) or 1 (almost clear).49,50 The IGA is a static evaluation recommended by the FDA for acne severity.6 The co-primary endpoints related to the face at week 12 and were (1) percentage of subjects achieving IGA scale success as defined above, (2) mean absolute change in facial inflammatory lesion count from baseline, and (3) mean absolute change in facial non-inflammatory lesion count from baseline.49,50 Co-secondary endpoints were the same indicators described previously but applied to assessment of the trunk and using the PGA scale.49,50 FDA guidance recommends limiting efficacy assessment to the face, as it is the most frequent site of involvement.6

All primary and secondary endpoints were statistically significant but no 95% confidence intervals were provided for any endpoint.50 (Table 8) PERFECT 1 had an overall IGA success of 29.4% for trifarotene, and 19.5% for placebo (ARR 9.9%/NNT 10) and PGA success of 35.7% for trifarotene, and 25.0% for placebo (ARR 10.7%/NNT 9) .50 Results for PERFECT 2 had higher IGA success rates in both groups, with 42.3% trifarotene and 25.7% placebo (ARR 16.6%/NNT 6) and PGA success of 42.6% trifarotene and 29.9% placebo (ARR 12.7%/NNT 8).50 Changes in inflammatory lesions, while statistically significant, included high placebo response rates of 35.7 to 51.2% across the various primary and secondary endpoints.50 These studies are of low quality, with limitations due to unclear selection bias in both trials and high attrition bias in PERFECT 1. Applicability is limited by low overall response rate in IGA, high placebo response rates in change of lesion count from baseline, and lack of diverse patient group.

Clinical Safety: Trifarotene cream causes erythema, scaling, dryness, and stinging/burning, reactions tend to be worse early in therapy and lessen over time.49,50 These adverse reactions were more common in the trifarotene group compared to the placebo group.49,50 (Table 6) Patients will also experience more sensitivity to sun exposure during treatment.49 Pregnant women were excluded from these phase III studies.49,50 Fetal adverse effects have been found in animal studies using 800-times the systemic exposure represented in these studies, and oral retinoid use is known to result in birth defects.49 There are no clinical data for use in lactation.49 An open-label continuation study of 1 year duration had 2.9% of patients experience an adverse reaction which led to treatment discontinuation.49

Author: Fletcher June 2020

Table 6: Application Site Tolerability Reactions at Any Post Baseline Visit (p values not reported)49 Face Trifarotene Vehicle cream (placebo) N=1214 N=1194 Maximum Severity during Treatment (% of patients) Maximum Severity during Treatment (% of patients) Mild Moderate Severe Mild Moderate Severe Erythema 30.6 28.4 6.2 21 6.8 0.8 Scaling 37.5 27.1 4.9 23.7 5.9 0.3 Dryness 39 29.7 4.8 29.9 6.8 0.8 Stinging/Burning 35.6 20.6 5.9 15.9 3.8 0.5 Trunk N=1202 N=1185 Erythema 26.5 18.9 5.2 12.7 4.4 0.4 Scaling 29.7 13.7 1.7 13.2 2.6 0.1 Dryness 32.9 16.1 1.8 17.8 3.9 0.1 Stinging/Burning 26.1 10.9 4.3 9.2 2.2 0.5

Comparative Endpoints: Clinically Meaningful Endpoints: Primary Study Endpoint: 1) Acne severity 1) IGA response 2) Number of inflammatory lesions 2) Inflammatory lesions 3) Number of non-inflammatory lesions 3) Non-inflammatory lesions 4) Quality of Life 5) Serious adverse events 6) Study withdrawal due to an adverse event

Table 7. Pharmacology and Pharmacokinetic Properties. Parameter Mechanism of Action Retinoic acid receptor agonist of gamma subtype Oral Bioavailability Topical (n/a) Distribution and Protein Binding 99.9% plasma protein bound Elimination Primarily feces Half-Life 2-9 hours Metabolism CYP2C9, CYP3A4, CYP3C8, CYP2B6 (minor)

Author: Fletcher June 2020

Table 8. Comparative Evidence Table. Ref./ Drug Regimens/ Patient Population N Efficacy Endpoints ARR/ Safety Outcomes ARR/NNH Risk of Bias/ Study Duration NNT Applicability Design 1. Tan et 1. Trifarotene Demographics: ITT: Primary Endpt (FACE) # (%): Severe AE N/A Risk of Bias (low/high/unclear): al49,50 cream 50 mcg/g Age (mean, SD): 19.4 ± 1. 612 IGA success (# of patients): Selection Bias: (unclear) randomization once daily at 6.41 2. 596 (2 point improvement AND T: 6 stratified by study center but described as Phase 3, bedtime x 12 Male: 579 (47.9%) overall score of clear to almost P: 0 both “interactive response technology” and DB, DB, weeks (T) White: 992 (82.1%) clear) “randomization list generated by statistician RCT Study w/d due to AE and provided to packaging organization for 2. Placebo vehicle Skin phototype Attrition: T:180 (29.4) 9.9%/ (%): labeling” PERFECT cream once daily Type I: 65 (5.4%) 1. 72 P: 116 (19.5) 10 T: 1.9% Performance Bias: (low) Topical medication in 1 at bedtime x 12 Type II: 379 (31.4%) (11.8%) p<0.001 (95% CI NR) P: 0% identical packaging, subjects instructed not to weeks (P) Type III: 460 (38.1%) 2. 61 discuss appearance of drug with NCT0256 Type IV: 188 (15.6%) (10.2%) Inflammatory lesions: investigators/evaluators; randomization list 6369 Both groups Type V: 91 (7.5%) Mean absolute Δ from baseline locked to non-designated personnel. instructed to Type VI: 25 (2.1%) T: -19 (-54.4) Detection Bias: (low) Assessors all trained in cleanse skin before P: -15.4 (-44.8) study-specific measurements and were application. Baseline lesions (Face) p<0.001 (95% CI NR) blinded. Patients were primarily assessed by Moisturizer use (mean ± SD) same evaluator during study for continuity. was encouraged, Inflammatory: 34.8 ± Noninflammatory lesions: Attrition Bias: (high) Discontinuation rate of but to be avoided 13.31 Mean absolute Δ from baseline 11% in short term study. Discontinuations due 1 hr before or Noninflammatory: 53.4 T: -25 (-49.7) 10.7% to “withdrawal by subject” not itemized by after study drug ±27.35 P: -17.9 (-35.7) /9 reason. Adverse events causing withdrawal application. p<0.001 (95% CI NR) were much more frequent in intervention Baseline lesions (Trunk) group. ITT analysis with multiple imputation Dosing could be Inflammatory: 35.3 Secondary Endpt (TRUNK) # (%): methodology used for missing values. changed by ±17.32 PGA success Reporting Bias: (low) All prespecified outcome investigator to Noninflammatory: 46.9 (2 point improvement AND presented, however, p-values reported every other day x 2 ± 21.75 overall score of clear to almost without CI. weeks, within first clear) Other Bias: (high) industry funded 4 weeks from baseline Key Inclusion Criteria: T: 214 (35.7) Applicability: assessment if -age ≥9 years P: 146 (25.0) Patient: Patients predominantly white and needed to manage -moderate facial acne p<0.001 (95% CI NR) with skin phototype I or II (of VI), limiting irritation. (IGA score 3, ≥20 applicability to other skin types (e.g. African- inflammatory lesions, Inflammatory lesions: Americans or Latinos). and ≥25 Mean absolute Δ from baseline Intervention: Intervention appropriate with noninflammatory T: -21.4 (-57.4) use of FDA approved product and allowance lesions) AND moderate P: -18.8 (-50.0) for home moisturizer use. truncal acne* (PGA p<0.001 (95% CI NR) Comparator: Placebo appropriate, but score of 3, ≥20 comparison with active comparator would inflammatory lesions, Noninflammatory lesions: enable comparative assessment of clinical and 20-99 Mean absolute Δ from baseline efficacy. noninflammatory T: -21.9 (-49.1) Outcomes: IGA/PGA and lesion count are lesions on trunk and P: -17.8 (-40.3) common outcomes in acne assessment. Author: Fletcher June 2020

reachable for self- p<0.001 (95% CI NR) Setting: Over 100 study sites across the application) United States, Canada, Russia, and Europe; all countries with a predominantly white *criterion waived for 9- population. 11 year olds due to rarity in this age group

Exclusion Criteria: -severe acne - >1 nodule on face - >1 nodule on trunk -presence of acne cysts, beard, facial hair, or tattoos that could interfere with assessments -uncontrolled or serious medical condition -significantly abnormal lab values -drug sensitivities -pregnancy, lactation, or intent to conceive 2. Tan et Identical to Demographics: ITT: Primary Endpt (FACE) # (%): Severe AE Risk of Bias (low/high/unclear): al49,50 PERFECT 1 above Age (mean, SD): 19.7 ± 1. 602 IGA success 16.6% (# of patients): See PERFECT 1 6.3 2. 610 Trifarotene 255 (42.3) /6 T: 3 Phase 3, 1. Trifarotene Male: 517 (42.7%) Placebo 157 (25.7) P: 0 Applicability: DB, DB, cream 50 mcg/g White: 1119 (92.3%) p<0.001 (95% CI NR) Patient: Patients predominantly white and RCT once daily at Attrition: Study w/d due to AE with skin phototype I or II (of VI), limiting bedtime x 12 Skin phototype 1. 44 (# of patients): applicability to other skin types (e.g. African- PERFECT weeks (T) Type I: 73 (6%) (7.3%) Inflammatory lesions: T: 1.2% Americans or Latinos). 2 Type II: 523 (43.2%) 2. 37 Mean absolute Δ from baseline P: 0% Intervention: Intervention appropriate 2. Placebo vehicle Type III: 481(39.7%) (6.1%) Trifarotene -24.2 (-66.2) Comparator: Placebo appropriate, but NCT0255 cream once daily Type IV: 71 (5.9%) Placebo -18.7 (-51.2) comparison with active comparator would 6788 at bedtime x 12 Type V: 33 (2.7%) p<0.001 (95% CI NR) enable comparative assessment of clinical weeks (P) Type VI: 31 (2.6%) efficacy. Noninflammatory lesions: Outcomes: IGA/PGA and lesion count are Both groups Baseline lesions (Face) Mean absolute Δ from baseline common outcomes in acne assessment. instructed to (mean ± SD) Trifarotene -30.1 (-57.7) Setting: Over 100 study sites across the cleanse skin before Inflammatory: 36.6 ± Placebo -21.6 (-43.9) United States, Canada, Russia, and Europe; all application. 13.84 p<0.001 (95% CI NR) countries with a predominantly white Moisturizer use Noninflammatory: 50.9 population. was encouraged, ±25.83 Secondary Endpt (TRUNK) # (%): but to be avoided PGA success 12.7% 1 hr before or Baseline lesions (Trunk) Trifarotene 255 (42.6) /8 Placebo 182 (29.9) Author: Fletcher June 2020

after study drug Inflammatory: 39.1 p<0.001 (95% CI NR) application. ±16.82 Noninflammatory: 45.9 Inflammatory lesions: Dosing could be ± 19.87 Mean absolute Δ from baseline changed by Trifarotene -25.5 (-65.4%) investigator to Placebo –19.8 (51.1) every other day x 2 Key Inclusion Criteria: p<0.001 (95% CI NR) weeks, within first -identical to PERFECT 1 4 weeks from Key Exclusion Criteria: Noninflammatory lesions: baseline -identical to PERFECT 1 Mean absolute Δ from baseline assessment if Trifarotene -25.9 (-55.2) needed to manage Placebo –20.8 (45.1%) irritation. p<0.001 (95% CI NR)

Abbreviations: AE = adverse event; ARR = absolute risk reduction; CI = confidence interval; IGA = Investigator’s Global Assessment; ITT = intention to treat; N = number of subjects; NA = not applicable; NNH = number needed to harm; NNT = number needed to treat; PGA = Physician’s Global Assessment; P = placebo vehicle cream group; PP = per protocol; SD = standard deviation; T = trifarotene group; w/d = withdrawal

References:

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Author: Fletcher June 2020

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30. Rea S, Tucker S, Frittelli V, Gunnarsson R. A feasibility study for a triple-blind randomized controlled trial investigating the effects of oral isotretinoin on mood and quality of life in patients with acne vulgaris. Clinical & Experimental Dermatology. 2018;43(1):54-56. 31. Tanghetti E, Harper J, Baldwin H, Kircik L, Bai Z, Alvandi N. Once-Daily Topical Dapsone Gel, 7.5%: Effective for Acne Vulgaris Regardless of Baseline Lesion Count, With Superior Efficacy in Females. Journal of Drugs in Dermatology: JDD.17(11):1192-1198. 32. Tanghetti EA, Kircik LH, Green LJ, et al. A Phase 2, Multicenter, Double-Blind, Randomized, Vehicle-Controlled Clinical Study to Compare the Safety and Efficacy of a Novel Tazarotene 0.045% Lotion and Tazarotene 0.1% Cream in the Treatment of Moderate-to-Severe Acne Vulgaris. Journal of Drugs in Dermatology: JDD.18(6):542. 33. Taylor SC, Cook-Bolden FE, McMichael A, et al. Efficacy, Safety, and Tolerability of Topical Dapsone Gel, 7.5% for Treatment of Acne Vulgaris by Fitzpatrick Skin Phototype. Journal of Drugs in Dermatology: JDD.17(2):160-167. 34. Tomic I, Juretic M, Jug M, Pepic I, Cetina Cizmek B, Filipovic-Grcic J. Preparation of in situ hydrogels loaded with azelaic acid nanocrystals and their dermal application performance study. International Journal of Pharmaceutics.563:249-258. 35. Yavuz C, Ozcimen M. An evaluation of peripapillar choroidal thickness in patients receiving systemic isotretinoin treatment. Cutaneous & Ocular Toxicology.38(1):25-28. 36. Zheng Y, Yin S, Xia Y, et al. Efficacy and safety of 2% supramolecular salicylic acid compared with 5% benzoyl peroxide/0.1% adapalene in the acne treatment: a randomized, split-face, open-label, single-center study. Cutaneous & Ocular Toxicology.38(1):48-54. 37. Cannizzaro MV, Dattola A, Garofalo V, Del Duca E, Bianchi L. Reducing the oral isotretinoin skin side effects: efficacy of 8% omega- ceramides, hydrophilic sugars, 5% niacinamide cream compound in acne patients. Giornale Italiano di Dermatologia e Venereologia.153(2):161-164. 38. Gencoglan G, Inanir I, Miskioglu M, Gunduz K. Evaluation of sequential effect of isotretinoin on the haematological parameters in patients with acne vulgaris. Cutan Ocul Toxicol. 2018;37(2):139-142. 39. Ghiasi M, Mortazavi H, Jafari M. Efficacy of Folic Acid and Vitamin B₁₂ Replacement Therapies in the Reduction of Adverse Effects of Isotretinoin: A Randomized Controlled Trial. SKINmed.16(4):239-245. 40. Hou JH, Shin H, Jang KH, et al. Anti-acne properties of hydrophobic fraction of red ginseng (Panax ginseng C.A. Meyer) and its active components. Phytotherapy Research.33(3):584-590. 41. In Jae J, Dong Ju H, Dong Hyun K, Yoon MS, Lee HJ. Comparative study of buffered 50% glycolic acid (pH 3.0) + 0.5% salicylic acid solution vs Jessner's solution in patients with acne vulgaris. Journal of Cosmetic Dermatology. 2018;17(5):797-801. 42. Kim MR, Kerrouche N. Combination of benzoyl peroxide 5% gel with liquid cleanser and moisturizer SPF 30 in acne treatment results in high levels of subject satisfaction, good adherence and favorable tolerability. Journal of Dermatological Treatment.29(1):49-54. 43. Pandey D, Agrawal S. Efficacy of Isotretinoin and Antihistamine versus Isotretinoin Alone in the Treatment of Moderate to Severe Acne: A Randomised Control Trial. Kathmandu University Medical Journal.17(65):14-19. 44. Stringer T, Nagler A, Orlow SJ, Oza VS. Clinical evidence for washing and cleansers in acne vulgaris: a systematic review. Journal of Dermatological Treatment.29(7):688-693. 45. Han G, Armstrong AW, Desai SR, Guenin E. Novel Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris in an Asian Population. Journal of Drugs in Dermatology: JDD.18(9):910-916. 46. Hayashi N, Kurokawa I, Siakpere O, et al. Clindamycin phosphate 1.2%/benzoyl peroxide 3% fixed-dose combination gel versus topical combination therapy of adapalene 0.1% gel and clindamycin phosphate 1.2% gel in the treatment of acne vulgaris in Japanese patients: A multicenter, randomized, investigator-blind, parallel-group study. Journal of Dermatology.45(8):951-962. Author: Fletcher June 2020

47. Dreno B, Bissonnette R, Gagne-Henley A, et al. Prevention and Reduction of Atrophic Acne Scars with Adapalene 0.3%/Benzoyl Peroxide 2.5% Gel in Subjects with Moderate or Severe Facial Acne: Results of a 6-Month Randomized, Vehicle-Controlled Trial Using Intra- Individual Comparison. American Journal of Clinical Dermatology.19(2):275-286. 48. Kovitwanichkanont T, Driscoll T. A comparative review of the isotretinoin pregnancy risk management programs across four continents. International Journal of Dermatology.57(9):1035-1046. 49. Aklief (trifarotene) Prescribing Information. Galderma Laboratories, L.P. Fort Worth, TX. Oct 2019. 50. Tan J, Thiboutot D, Popp G, et al. Randomized phase 3 evaluation of trifarotene 50 mug/g cream treatment of moderate facial and truncal acne. J Am Acad Dermatol. 2019;80(6):1691-1699.

Author: Fletcher June 2020

Appendix 1: Current Preferred Drug List

Generic Brand Form Route PDL adapalene ADAPALENE CREAM (G) TP Y adapalene DIFFERIN CREAM (G) TP Y adapalene ADAPALENE GEL (GRAM) TP Y adapalene DIFFERIN GEL (GRAM) TP Y adapalene ADAPALENE GEL W/PUMP TP Y adapalene DIFFERIN GEL W/PUMP TP Y adapalene DIFFERIN LOTION TP Y adapalene/benzoyl peroxide ADAPALENE-BENZOYL PEROXIDE GEL W/PUMP TP Y adapalene/benzoyl peroxide EPIDUO GEL W/PUMP TP Y azelaic acid AZELAIC ACID GEL (GRAM) TP Y azelaic acid FINACEA GEL (GRAM) TP Y benzoyl peroxide BENZOYL PEROXIDE CLEANSER TP Y benzoyl peroxide PACNEX CLEANSER TP Y benzoyl peroxide ACNE MEDICATION GEL (GRAM) TP Y benzoyl peroxide BENZAC W 10 GEL (GRAM) TP Y benzoyl peroxide BENZAC W 2.5 GEL (GRAM) TP Y benzoyl peroxide BENZAC W 5 GEL (GRAM) TP Y benzoyl peroxide BENZOYL PEROXIDE GEL (GRAM) TP Y benzoyl peroxide DEL-AQUA-5 GEL (GRAM) TP Y benzoyl peroxide PANOXYL AQ 2.5 GEL (GRAM) TP Y benzoyl peroxide PANOXYL AQ 5 GEL (GRAM) TP Y benzoyl peroxide BPO TOWELETTE TP Y clindamycin phos/benzoyl perox BENZACLIN GEL (GRAM) TP Y clindamycin phos/benzoyl perox CLINDAMYCIN PHOS-BENZOYL PEROX GEL (GRAM) TP Y clindamycin phos/benzoyl perox CLINDAMYCIN-BENZOYL PEROXIDE GEL (GRAM) TP Y clindamycin phos/benzoyl perox DUAC GEL (GRAM) TP Y clindamycin phos/benzoyl perox NEUAC GEL (GRAM) TP Y clindamycin phos/benzoyl perox ACANYA GEL W/PUMP TP Y clindamycin phos/benzoyl perox BENZACLIN GEL W/PUMP TP Y clindamycin phos/benzoyl perox CLINDAMYCIN PHOS-BENZOYL PEROX GEL W/PUMP TP Y clindamycin phos/benzoyl perox CLINDAMYCIN-BENZOYL PEROXIDE GEL W/PUMP TP Y clindamycin phosphate CLINDAMYCIN PHOSPHATE FOAM TP Y clindamycin phosphate EVOCLIN FOAM TP Y clindamycin phosphate CLEOCIN T GEL (GRAM) TP Y clindamycin phosphate CLINDAMYCIN PHOSPHATE GEL (GRAM) TP Y clindamycin phosphate CLEOCIN T LOTION TP Y Author: Fletcher June 2020

clindamycin phosphate CLINDAMYCIN PHOSPHATE LOTION TP Y clindamycin phosphate CLEOCIN T MED. SWAB TP Y clindamycin phosphate CLINDACIN ETZ MED. SWAB TP Y clindamycin phosphate CLINDACIN P MED. SWAB TP Y clindamycin phosphate CLINDAMYCIN PHOSPHATE MED. SWAB TP Y clindamycin phosphate CLINDAMYCIN PHOSPHATE SOLUTION TP Y clindamycin/tretinoin CLINDAMYCIN PHOS-TRETINOIN GEL (GRAM) TP Y clindamycin/tretinoin ZIANA GEL (GRAM) TP Y dapsone ACZONE GEL (GRAM) TP Y dapsone DAPSONE GEL (GRAM) TP Y erythromycin base in ethanol ERYGEL GEL (GRAM) TP Y erythromycin base in ethanol ERYTHROMYCIN GEL (GRAM) TP Y erythromycin base in ethanol ERY MED. SWAB TP Y erythromycin base in ethanol ERYTHROMYCIN MED. SWAB TP Y erythromycin base in ethanol ERYTHROMYCIN SOLUTION TP Y isotretinoin ABSORICA CAPSULE PO Y isotretinoin AMNESTEEM CAPSULE PO Y isotretinoin CLARAVIS CAPSULE PO Y isotretinoin ISOTRETINOIN CAPSULE PO Y isotretinoin MYORISAN CAPSULE PO Y isotretinoin ZENATANE CAPSULE PO Y sulfacetamide sodium KLARON SUSPENSION TP Y sulfacetamide sodium SULFACETAMIDE SODIUM SUSPENSION TP Y tretinoin AVITA CREAM (G) TP Y tretinoin RETIN-A CREAM (G) TP Y tretinoin TRETINOIN CREAM (G) TP Y tretinoin ATRALIN GEL (GRAM) TP Y tretinoin AVITA GEL (GRAM) TP Y tretinoin RETIN-A GEL (GRAM) TP Y tretinoin TRETINOIN GEL (GRAM) TP Y tretinoin microspheres RETIN-A MICRO GEL (GRAM) TP Y tretinoin microspheres TRETINOIN MICROSPHERE GEL (GRAM) TP Y tretinoin microspheres RETIN-A MICRO PUMP GEL W/PUMP TP Y tretinoin microspheres TRETINOIN MICROSPHERE GEL W/PUMP TP Y adapalene PLIXDA MED. SWAB TP N adapalene ADAPALENE SOLUTION TP N adapalene/benzoyl peroxide EPIDUO FORTE GEL W/PUMP TP N azelaic acid AZELEX CREAM (G) TP N azelaic acid FINEVIN CREAM (G) TP N azelaic acid FINACEA FOAM TP N Author: Fletcher June 2020

benzoyl peroxide PANOXYL CLEANSER TP N benzoyl peroxide PANOXYL-4 CLEANSER TP N benzoyl peroxide BPO GEL (GRAM) TP N clindamycin phos/benzoyl perox ONEXTON GEL (GRAM) TP N clindamycin phos/benzoyl perox ONEXTON GEL W/PUMP TP N clindamycin phos/skin clnsr 19 CLINDACIN ETZ KIT TP N clindamycin phos/skin clnsr 19 CLINDACIN PAC KIT TP N clindamycin phosphate CLINDAGEL GEL DAILY TP N clindamycin phosphate CLINDAMYCIN PHOSPHATE GEL DAILY TP N clindamycin/benzoyl/emol cmb94 NEUAC CMB CR GEL TP N dapsone ACZONE GEL W/PUMP TP N erythromycin/benzoyl peroxide BENZAMYCIN GEL (GRAM) TP N erythromycin/benzoyl peroxide ERYTHROMYCIN-BENZOYL PEROXIDE GEL (GRAM) TP N isotretinoin ABSORICA CAPSULE PO N tazarotene FABIOR FOAM TP N tretinoin TRETIN-X CREAM (G) TP N tretinoin microspheres RETIN-A MICRO PUMP GEL W/PUMP TP N tretinoin/emol 9/skin cleansr1 TRETIN-X COMBO. PKG TP N trifarotene AKLIEF CREAM (G) TP N benzoyl peroxide BENZOYL PEROXIDE CLEANSER TP benzoyl peroxide PANOXYL CLEANSER TP benzoyl peroxide CLEARASIL DAILY CLEAR CREAM (G) TP benzoyl peroxide DEL-AQUA-10 CREAM (G) TP benzoyl peroxide ACNE MEDICATION LOTION TP benzoyl peroxide BENZOYL PEROXIDE LOTION TP tretinoin ALTRENO LOTION TP

Author: Fletcher June 2020

Appendix 2: Abstracts of Comparative Clinical Trials

A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: Results of 2 randomized, double-blind, phase 3 studies Gold LS, Dhawan S, Weiss J, Draelos ZD, Ellman H, Stuart IA

Background FMX101 4% is a topical minocycline foam for the treatment of moderate-to-severe acne. Objective Evaluate the efficacy and safety of FMX101 4% in treating moderate-to-severe acne vulgaris. Methods Two identical phase 3 studies were conducted. Subjects were randomized 2:1 to once-daily FMX101 4% or foam vehicle for 12 weeks. The coprimary end points were the change in inflammatory lesion count from baseline and the rate of treatment success according to the Investigator's Global Assessment (a score of 0 or 1 for clear or almost clear, with a ≥2-grade improvement) at week 12. Results A total of 961 subjects were enrolled (study 04, N = 466; study 05, N = 495). Compared with vehicle, FMX101 4% demonstrated a significantly greater reduction in inflammatory lesions in both studies (P < .05) and a greater rate of treatment success in study 05 according to the Investigator's Global Assessment (P < .05). Pooled analyses of the 2 studies demonstrated statistical significance for both coprimary end points (all P < .05). Noninflammatory lesion count was also significantly reduced with FMX101 4% versus with vehicle in both studies. FMX101 4% was generally safe and well tolerated. Skin-related adverse events were reported in less than 1% of subjects treated with FMX101 4%. Limitations Longer-term efficacy and safety outcomes are needed (ongoing). Conclusion FMX101 4% topical minocycline foam significantly reduced both inflammatory and noninflammatory lesions and improved Investigator's Global Assessment scores in patients with moderate-to-severe acne. J Am Acad Dermatol 2019;80:168-77 https://doi.org/10.1016/j.jaad.2018.08.020

Novel Tretinoin 0.05% Lotion for the Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Assessment of Efficacy and Safety in Patients Aged 9 Years and Older Tyring SK, Kircik LH, Pariser DM, Guenin E, Bhatt V, Pillai R

Background Topical tretinoin has been extensively studied in clinical trials, and its essential role in the treatment of acne vulgaris (acne) established through evidence-based guidelines. Objective To evaluate efficacy, safety, and tolerability of a novel tretinoin 0.05% lotion in moderate-to-severe acne in patients aged 9 years and older. Methods: A total of 1640 patients, 9-58 years of age were randomized to receive tretinoin 0.05% lotion or vehicle in two double-blind, placebo-controlled 12-week, 2-arm, parallel group studies evaluating safety and efficacy (inflammatory and noninflammatory lesion counts and acne severity using Evaluator Global Severity Scores [EGSS]). Author: Fletcher June 2020

In addition, patients completed a patient satisfaction survey (PSS), Acne-specific quality of life (QoL) questionnaire and assessed their facial skin for shininess/oiliness improvement. The data from these two independent studies were pooled and analyzed. Results Tretinoin 0.05% lotion demonstrated statistically significant superiority to vehicle in reducing inflammatory and noninflammatory lesion counts (both P less than .001) at week 12 and improving acne severity (P less than .001). At week 12, mean percent change in inflammatory and noninflammatory lesions were 52% and 46%, respectively. Treatment success (a 2-grade improvement in EGSS and ‘clear’ or ‘almost clear’ was reported in 18% of patients. Tretinoin 0.05% lotion also showed significantly greater benefits relative to vehicle control in terms of patient satisfaction (P less than .001) and acne-specific QoL domains. Tretinoin 0.05% lotion was very well tolerated with no substantive differences in cutaneous tolerability among treatment groups. No patients discontinued treatment because of adverse events. Limitations Data from controlled studies may differ from clinical practice. Conclusions: Tretinoin 0.05% lotion provides statistically significant greater efficacy than vehicle with a highly favorable safety and tolerability profile in moderate-to-severe acne patients. J Drugs Dermatol. 2018;17(10):1084-1091.

Author: Fletcher June 2020

Appendix 3: Medline Search Strategy Step Search Term Article # 1 Adapalene/tu, to [Therapeutic Use, Toxicity] 20 2 azelaic acid.mp. 721 3 Benzoyl Peroxide/tu, to [Therapeutic Use, Toxicity] 511 4 Clindamycin/tu, to [Therapeutic Use, Toxicity] 2840 5 Dapsone/tu, th, to [Therapeutic Use, Therapy, Toxicity] 2890 6 Erythromycin/tu, th, to [Therapeutic Use, Therapy, Toxicity] 4499 7 Isotretinoin/tu, to [Therapeutic Use, Toxicity] 1438 8 Sulfacetamide/tu, th, to [Therapeutic Use, Therapy, Toxicity] 109 9 Tretinoin/tu, to [Therapeutic Use, Toxicity] 4089 10 tazarotene.mp. 565 11 trifarotene.mp. 10 12 Contraceptives, Oral/tu, th, to [Therapeutic Use, Therapy, Toxicity] 1542 13 Acne Vulgaris/dt, pc, th [Drug Therapy, Prevention & Control, Therapy] 6727 14 Acne Conglobata/dt, th [Drug Therapy, Therapy] 5 15 acne fulminans.mp. 178 16 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 18477 13 or 14 or 15 17 6816 18 16 and 17 1792 19 limit 18 to (english language and yr="2018 -Current" and (clinical trial, all or clinical trial, phase iii or clinical trial, phase iv or 28 clinical trial or comparative study or controlled clinical trial or guideline or meta analysis or multicenter study or practice guideline *24 after duplicates removed or pragmatic clinical trial or randomized controlled trial or "systematic review")) Additional articles found via hand searching of reviews.

Author: Fletcher June 2020

Appendix 4: Prescribing Information Highlights

Author: Fletcher June 2020

Appendix 5: Key Inclusion Criteria

Population Adults and children with acne conglablata, acne fulminans, or severe acne vulgaris Intervention Trifarotene topical therapy, other acne therapies (see appendix 3) Comparator Placebo or active treatment Outcomes Inflammatory and noninflammatory lesion reduction, adverse reactions Timing Not applicable Setting Outpatient therapy

Author: Fletcher June 2020

Appendix 6: Prior Authorization Criteria Acne Medications Goal(s):  Ensure that medications for acne are used appropriately for OHP-funded conditions.

Length of Authorization:  Up to 12 months

Requires PA:  All drugs in the Acne medications class

Covered Alternatives:  Current PMPDP preferred drug list per OAR 410-121-0030 at www.orpdl.org  Searchable site for Oregon FFS Drug Class listed at www.orpdl.org/drugs/

Approval Criteria

1. What diagnosis is being treated? Record ICD10 code.

2. Is the request for an FDA-approved indication? Yes: Go to #3 No: Pass to RPh. Deny; medical appropriateness

3. Is the diagnosis funded by OHP? Yes: Go to #4 No: Pass to RPh. Deny; not funded by the OHP.

4. Will the prescriber consider a change to a preferred Yes: Inform prescriber of No: Approve for 12 months. product? covered alternatives in class and process appropriate PA.. Message:  Preferred products are evidence-based reviewed for comparative effectiveness and safety by the Oregon Pharmacy & Therapeutics Committee.

P&T/DUR Review: 06/2020 (SF); 11/18 (JP) Implementation: (TBD); 1/1/1 Author: Fletcher June 2020